Context The Women's Health Initiative Memory Study (WHIMS) previously found
increased risk for dementia and no effect on mild cognitive impairment (MCI)
in women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone
acetate (MPA).
Objective To determine the effects of CEE alone and CEE plus MPA on incidence
of probable dementia and MCI in older women.
Design, Setting, and Participants Randomized, double-blind, placebo-controlled clinical trials of CEE
(estrogen-alone trial) or CEE plus MPA (estrogen plus progestin trial) in
community-dwelling women aged 65 to 79 years, conducted from June 1995 to
July 8, 2002 (estrogen plus progestin; n = 4532), or to February 29, 2004
(estrogen-alone; n = 2947), in 39 of the 40 WHI clinical centers.
Interventions In the estrogen-alone trial, 1 daily tablet containing either 0.625
mg/d of CEE vs matching placebo; in the estrogen plus progestin trial, 1 daily
tablet containing CEE (0.625 mg/d) plus MPA (2.5 mg/d) vs matching placebos.
Main Outcome Measures Probable dementia and MCI.
Results In the estrogen-alone trial, 47 participants were diagnosed with probable
dementia, of whom 28 were assigned to CEE and 19 to placebo (hazard ratio
[HR], 1.49; 95% confidence interval [CI], 0.83-2.66). Incidence rates for
probable dementia in the estrogen-alone trial were statistically similar to
those in the estrogen plus progestin trial (45 vs 22 per 10 000 person-years
for CEE plus MPA vs placebo, respectively; P = .11).
When data were pooled per the original WHIMS protocol, the overall HR for
probable dementia was 1.76 (95% CI, 1.19-2.60; P =
.005). After excluding participants with baseline Modified Mini-Mental State
Examination scores at or below the screening cut point, the HR was 1.77 (95%
CI, 0.74-4.23; P = .20) in the estrogen-alone trial
and 2.19 (95% CI, 1.25-3.84; P = .006) in the pooled
trials. In the estrogen-alone trial, 76 participants were diagnosed with MCI
in the CEE group vs 58 in the placebo group (HR, 1.34; 95% CI, 0.95-1.89).
In the combined trial data, the HR was similar (1.25; 95% CI, 0.97-1.60).
In the estrogen-alone trial, 93 participants receiving CEE were diagnosed
with either probable dementia or MCI vs 69 receiving placebo (HR, 1.38; 95%
CI, 1.01-1.89; P = .04).
Conclusions Estrogen therapy alone did not reduce dementia or MCI incidence and
increased the risk for both end points combined. Pooling data for estrogen
alone and estrogen plus progestin resulted in increased risks for both end
points. Use of hormone therapy to prevent dementia or cognitive decline in
women 65 years of age or older is not recommended.
Dementia is an age-associated illness that imposes severe functional
impairment on individuals. In 2000, more than 4 million people in the United
States had Alzheimer disease (AD), and that number is expected to increase
to 13 million by 2050.1 Milder cognitive impairment
affects between one fifth and one third of older adults2 and
strongly predicts dementia and subsequent institutionalization.3 Case-control
studies,4,5 cross-sectional studies,6 and prospective studies7-9 have
reported an association between lower risk of dementia and postmenopausal
estrogen supplementation. Meta-analyses of the potential protective effects
of estrogen against dementia have reported risk reductions of 29%10 and 34%.11 However,
prospective observational studies have not found a protective effect of estrogen
on either cognition or the incidence of dementia.12,13 In
addition, clinical trials of unopposed estrogen in women with AD showed no
benefit on cognitive performance,14-16 and
methodological limitations, including the paucity of large, controlled clinical
trials, have prevented clear conclusions.17,18 The
mixed findings to date leave unanswered questions about the efficacy of estrogen
therapy in preventing cognitive decline and dementia in postmenopausal women.
The Women's Health Initiative Memory Study (WHIMS)19 is
a large, randomized, double-blind, placebo-controlled clinical trial examining
whether postmenopausal hormone therapy (estrogen alone or estrogen plus progestin)
reduces the risk of dementia in healthy women aged 65 to 79 years at baseline.
The WHIMS is an ancillary study to the larger Women's Health Initiative (WHI)
randomized clinical trials of hormone therapy that include a geographically
diverse group of approximately 27 000 women. The estrogen plus progestin
trial of the WHI was terminated in July 2002 due to significantly more noncognitive
adverse events associated with conjugated equine estrogens (CEE) plus medroxyprogesterone
acetate (MPA) compared with placebo.20 The
WHI estrogen-alone trial was terminated on February 29, 2004, because the
National Institutes of Health considered the excess risk of stroke in the
active hormone group to be unacceptable in healthy women in the absence of
benefit for coronary heart disease, the primary outcome.21
The objective of the WHIMS was to evaluate whether CEE or CEE plus MPA
vs matching placebos decrease women's risk for dementia.
WHI Hormone Therapy Trials
WHIMS participants initially met eligibility requirements, provided
written informed consent, and enrolled in the WHI estrogen-alone trial (for
women with prior hysterectomy) or the WHI estrogen plus progestin trial, and
were randomized to receive either CEE, CEE plus MPA, or matching placebos
(Wyeth Pharmaceuticals, Philadelphia, Pa).22 In
the estrogen-alone trial, women aged 50 to 79 years at baseline with a prior
hysterectomy were screened for eligibility.22 Those
who had previously taken postmenopausal hormone therapy underwent a 3-month
washout before initial screening.
Randomization was determined using a permuted block algorithm that was
stratified by age and clinical center by the WHI Clinical Coordinating Center
(CCC) at the Fred Hutchinson Cancer Research Center, Seattle, Wash. Study
pills were dispensed and safety and outcomes assessments took place semiannually,
and participants returned for clinic visits annually.
WHIMS Participant Enrollment
WHI participants eligible for the WHIMS were 65 to 79 years of age at
baseline and free of probable dementia as ascertained by the WHIMS protocol.19 Of 3200 age-eligible WHI participants, 2947 (92.1%)
consented to participate and enrolled in the estrogen-alone trial. Similarly,
of the 4894 women approached for the estrogen plus progestin trial, 4532 (92.6%)
consented. Study coordination for the WHIMS was provided by the WHIMS CCC
at Wake Forest University School of Medicine, Winston-Salem, NC.
The National Institutes of Health and the institutional review boards
for the WHI CCC and each WHI clinical center approved the WHI and WHIMS protocols
and consent forms. Monitoring of the WHI hormone therapy trials was conducted
semiannually by an independent data and safety monitoring board. Trial monitoring
guidelines for early stopping considerations have been published.20
WHIMS Protocol for Detecting Probable Dementia and Mild Cognitive Impairment
A detailed description of the WHIMS protocol for detecting probable
dementia and mild cognitive impairment (MCI) has been published.19 The
protocol consisted of 4 phases. In phase 1, participants underwent a cognitive
screening with the Modified Mini-Mental State Examination (3MSE)23 at
baseline and annually thereafter. Women who scored below an education-adjusted
cut point on the 3MSE (≤72 for those with ≤8 years of formal education
and ≤76 for those with ≥9 years of education; to increase sensitivity,
after 16 months new cut points of ≤80 for those with ≤8 years of education
and ≤88 for those with ≥9 years of education were implemented prospectively24) underwent phase 2 of the WHIMS, including a modified
Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery
of neuropsychological tests25 and standardized
interviews to assess acquired cognitive and behavioral impairments.26,27 In addition, a designated informant
(friend or family member) was interviewed separately regarding acquired cognitive
and behavioral impairments in the participant.
After completing phase 2, participants were evaluated by a local physician-specialist
with experience in diagnosing dementia (phase 3). Using a standardized protocol
provided by the WHIMS CCC, local physicians reviewed all available data and
performed a clinical neuropsychiatric evaluation. The physician then classified
the WHIMS participant as having no dementia, MCI, or probable dementia, based
on Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV) criteria.28 Our MCI classification was based on accepted criteria29 at the time the WHIMS was initiated and was operationally
defined as poor performance (10th or lower percentile based on CERAD norms30) on at least 1 CERAD test, a report of some functional
impairment (but not severe enough to interfere with basic activities of daily
living such as eating, dressing, grooming, etc) from the designated informant,
no evidence of a psychiatric disorder or medical condition that could account
for the decline in cognitive function, and an absence of adjudicated dementia.
Women suspected of having probable dementia underwent phase 4, including a
noncontrast computed tomography brain scan and laboratory blood tests to rule
out possible reversible causes of cognitive decline. If dementia was still
suspected, the physician was required to provide the most probable etiology
based on DSM-IV criteria for AD, vascular dementia
(VaD), and other dementia-related classifications. All clinical and test data
were then transmitted to the WHIMS CCC for review and central adjudication.
Central Adjudication of Probable Dementia and MCI
The central adjudication committee consists of 3 board-certified specialists
(2 neurologists and 1 geriatric psychiatrist) with extensive experience in
dementia. All cases judged as probable dementia by the local physician-specialists
were independently reviewed by the central adjudicators, as well as 50% of
MCI cases and 10% of cases without dementia. All test scores, lab test results,
and other data on the WHIMS participant, except the field physician's classification,
were provided to 2 adjudicators who independently evaluated the data and assigned
a classification. The field physician's diagnostic assessment was then shared
with each adjudicator, who could revise his or her diagnosis. If both adjudicators
agreed, the consensus diagnosis was recorded. If the adjudicators disagreed,
they discussed the case and if consensus was not achieved, the 3 adjudicators
plus a geriatric psychologist familiar with the neuropsychological measures
discussed the case until a consensus was reached. The same process was followed
to reach consensus on the etiologic classification of dementia.
Quality Assurance of Data
Audiotapes of the WHIMS neuropsychological test battery and copies of
the completed test booklets were sent to the WHIMS CCC. These materials were
closely reviewed for administration and/or scoring errors, and written feedback
was provided to technicians, who were recertified every 6 months.
All WHIMS-certified technicians, local WHIMS physicians, and WHIMS adjudicators
were blinded to participants' treatment assignment. Official unblinding at
the clinical sites to address safety concerns was handled by a designated
unblinding officer, who was the only individual authorized to access unblinding
information in the WHI database and to provide this information to the clinic's
consulting gynecologist. The adjudicators were independent of the clinical
center physicians and data provided to them were blinded.
Adherence data on hormone(s) were collected annually after randomization.
According to WHI criteria, a participant became nonadherent by (1) stopping
study medication for any reason, whether by personal decision or for protocol-based
safety issues; (2) taking less than 80% of her pills between dispensation
and collection; or (3) starting prescribed hormone(s) outside of the main
WHI hormone therapy trials. For these 3 criteria, the earliest nonadherence
date was selected and follow-up data were censored 6 months later for secondary
analyses examining the effect of nonadherence.
The WHIMS was designed to provide more than 80% statistical power to
detect an observed 40% relative reduction in all-cause dementia associated
with either CEE or CEE plus MPA vs matched placebos.19 Based
on a projected enrollment of 8300 women, approximately 165 cases of all-cause
dementia were expected over 5 years. When the estrogen-alone trial ended,
there were 47 cases of all-cause dementia. Post hoc calculations indicate
that the WHIMS estrogen-alone trial provided 80% statistical power to detect
a hazard ratio (HR) of 2.07 at the 5% significance level. Survival analyses
were conducted using intention-to-treat principles for the 2947 WHIMS estrogen-alone
participants and for all 7479 participants. Analyses included all WHI participants
who agreed to participate in the WHIMS, and treatment groups were based on
their randomization assignment in the WHI hormone therapy trials. For the
estrogen-alone analyses, all events up to termination of the study drug in
the WHI estrogen-alone trial (February 29, 2004) were included in the analyses
and were adjudicated as described above. Women who had MCI at baseline were
excluded in the analyses of MCI and its combination with probable dementia.
Hazard ratios and nominal 95% confidence intervals (CIs) from unadjusted
Cox proportional hazard models31 were compared
between the treatment and placebo groups. The time to event was defined as
the number of days from randomization into the WHI trial to the date of the
3MSE that triggered the referral for additional cognitive testing resulting
in the first postrandomization diagnosis. Participants without a diagnosis
were censored at their last follow-up contact: before February 29, 2004, for
the estrogen-alone trial and before July 8, 2002, for the estrogen plus progestin
trial. Cumulative hazards are presented. Secondary analyses were conducted
for participants with a diagnosis of MCI only, and either probable dementia
or MCI. Cox proportional hazard models were fitted separately with treatment
assignment and 1 of the following baseline factors as independent variables:
age; education; race; smoking; self-reported history of cardiovascular disease,
stroke, diabetes, or hypertension; prior use of hormone therapy, unopposed
estrogen, statins (ie, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A
[HMG-CoA]), or aspirin; and baseline 3MSE scores. In each of the 13 models,
the interaction between treatment assignment and the factor was tested; HRs
are presented for subgroups defined by these factors. A Bonferroni adjustment
was used to control for type I error (P = .05/13
[.004]). Secondary analyses also were conducted, censoring participants 6
months after they became nonadherent. A significance level of .05 was used
for analyses other than the 13 models. Analyses were conducted with SAS statistical
software (SAS Institute Inc, Cary, NC).
Figure 1 depicts the enrollment
and referrals to phases 2 through 4 for the estrogen-alone trial and for the
pooled estrogen-alone and estrogen plus progestin trials. In the estrogen-alone
trial, among those assigned to CEE, 184 participants were referred for further
cognitive testing a total of 346 times; among the women assigned to placebo,
172 participants were referred 300 times. Of the 80 participants who refused
further testing at least once, 13 (16%) had subsequent visits at which a diagnosis
was obtained, and of the 86 participants with incomplete data, 11 (13%) also
had a diagnosis from a subsequent visit. Overall, the percentages of women
ever referred were 12.6% (CEE) and 11.6% (placebo) in the estrogen-alone trial,
and 7.9% (CEE plus MPA) and 6.1% (placebo) in the estrogen plus progestin
trial.24
The average time between the last 3MSE and the date of randomization
into WHI for women in the estrogen-alone trial was 5.21 (SD, 1.73) years,
compared with 4.05 (SD, 1.19) years among women in the estrogen plus progestin
trial.
Table 1 lists the distribution
of risk factors for dementia at the time of WHI assignment for the participants
in the estrogen-alone trial. No significant differences between the CEE and
placebo groups were evident, except for the higher prevalence of hypertension
(P = .01) in the CEE group. This difference in hypertension
was maintained when combining women in both trials (Table 1). When compared with the women receiving estrogen plus progestin,
women receiving estrogen alone were relatively less educated, had lower 3MSE
scores at baseline, were more ethnically diverse, and were more likely to
have had a history of stroke syndrome or coronary heart disease and to have
used hormone therapy previously (P<.001 for all).
In the estrogen-alone trial, 47 participants were diagnosed with probable
dementia, of whom 28 were assigned to receive CEE and 19 to receive matching
placebo (Table 2). During follow-up,
the incidence of probable dementia was 49% higher among women assigned to
receive CEE compared with those receiving placebo (37 vs 25 per 10 000
person-years) (Figure 2A). This
negative trend did not reach statistical significance (P = .18). Incidence rates for probable dementia in the estrogen-alone
trial were statistically similar to those in the estrogen plus progestin trial
(45 vs 22 per 10 000 person-years for CEE plus MPA vs matching placebo,
respectively; P = .11). In addition, the HR associated
with assignment to active therapy in the estrogen-alone trial (1.49; 95% CI,
0.83-2.66) did not differ statistically from that for the estrogen plus progestin
trial (2.05; 95% CI, 1.21-3.48) (P = .44), although
the estrogen-alone HR was not significant. When data from the 2 trials were
pooled, the overall HR for probable dementia was 1.76 (95% CI, 1.19-2.60; P = .005) (Figure 2B).
After excluding participants with baseline 3MSE scores at or below the cut
point (overall n =553), the HR was 1.77 (95% CI, 0.74-4.23; P = .20) in the estrogen-alone trial and 2.19 (95% CI, 1.25-3.84; P = .006) in the pooled trials.
In the estrogen-alone trial, 42 participants in the placebo group experienced
stroke during the trial compared with 39 in the CEE group. Only 1 participant
experiencing a stroke in each group was classified with probable dementia.
After deleting all participants who experienced a centrally adjudicated stroke
during the trial, the HR for probable dementia was 1.51 (95% CI, 0.83-2.74; P = .18).
The distribution of types of dementia differed little between women
assigned to CEE vs placebo in the estrogen-alone trial (Table 3). Of the dementia cases, overall 47% were classified as
AD, 8.5% as VaD, and 19% as mixed type (having features of both AD and VaD).
In the pooled data, the distribution of dementia classifications was similar:
52% AD, 9% VaD, and 16% mixed type.
Local Clinician Diagnoses
Diagnoses from local clinicians were compared with those from central
adjudicators (Table 4). Agreement
between local clinicians and adjudicators was 75% in the estrogen-alone trial
(κ = 0.60; 95% CI, 0.52-0.68) and 77% in the estrogen plus progestin
trial (κ = 0.63; 95% CI, 0.58-0.69) (Table 4). Results were not affected by treatment assignment (P = .49). Most disagreements resulted in a less serious
classification by the central adjudicators in both intervention groups (P = .14). In the estrogen-alone trial, 56 cases were diagnosed
with probable dementia by local clinicians, 31 in the CEE group and 25 in
the placebo group, yielding an HR of 1.26 (95% CI, 0.74-2.12; P = .40). In the combined trials, the HR was 1.54 (95% CI, 1.08-2.21; P = .02).
In the estrogen-alone trial (as with the estrogen plus progestin trial),
adherence decreased over time. For CEE and placebo, respectively, adherence
rates were 77.2% and 84.1% (year 1), 66.3% and 71.6% (year 2), 59.8% and 63.1%
(year 3), 52.9% and 57.8% (year 4), 45.6% and 52.1% (year 5), 42.0% and 47.8%
(year 6), and 36.8% and 45.1% (year 7). In analyses limited to data censored
6 months after each participant's first assessed nonadherence, the HR for
probable dementia associated with CEE was 1.55 (95% CI, 0.49-4.88; P = .45). Similar analyses of pooled data yielded an HR associated
with hormone therapy of 2.38 (95% CI, 1.16-4.92; P =
.02).
Mild Cognitive Impairment
Seventy-six participants were diagnosed with MCI in the CEE group, compared
with 58 in the placebo group. The risk of being diagnosed with MCI in the
CEE group was 34% higher than in the placebo group (HR, 1.34; 95% CI, 0.95-1.89).
In the combined trials, the risk was similar (HR, 1.25, 95% CI, 0.97-1.60).
Neither HR was statistically significant.
Of the women assigned to CEE, 93 were classified as having either MCI
or probable dementia at some time during the trial, compared with 69 women
assigned to placebo (Table 5).
The incidence rates (per 10 000 person-years) of this composite end point
were 126 and 91 for women assigned to CEE and placebo, respectively; the relative
hazard associated with CEE was 1.38 (95% CI, 1.01-1.89; P = .04). These differences tended to emerge earlier than those for
probable dementia (Figure 3A). These
results did not differ significantly from those for the estrogen plus progestin
trial (P = .90) (Figure 3B). The HR for this composite end point was 1.41 for the
pooled data (95% CI, 1.12-1.76; P = .003).
Table 6 depicts the consistency
of HRs from the estrogen-alone trial across subgroups defined by baseline
risk factors for probable dementia. No significant heterogeneity was detected
(P>.004 for all). These findings parallel those for
the combined trials (Table 6).
Previous preclinical, epidemiologic, and clinical trial data suggested
that hormone therapy could benefit cognition and dementia among women with
perimenopausal symptoms and postmenopausal women with dementia.32 In
the WHIMS, the first double-blind, placebo-controlled, long-term multicenter
study of CEE and CEE plus MPA in postmenopausal women, both CEE and CEE plus
MPA were associated with an increased incidence of dementia compared with
placebo, although the association did not reach statistical significance in
the smaller, but longer, estrogen-alone trial.
The number of MCI classifications in the treatment groups of the WHIMS
trials were different (100 per 10 000 women for the estrogen-alone trial
vs 63 per 10 000 women for the estrogen plus progestin trial). When risks
of dementia and MCI were combined, effects of CEE and CEE plus MPA, compared
with matching placebos, were similar in both hormone therapy trials. In general,
MCI, particularly amnestic MCI, is viewed by most investigators as part of
a continuum from normal cognitive functioning to dementia. The WHIMS classification
of MCI required abnormality in any cognitive domain. Thus, it is possible
that some women may have a nonamnestic type of cognitive impairment, not necessarily
associated with an increased risk of dementia.2 Reanalyses
of the WHIMS classifications of MCI into amnestic and nonamnestic types may
provide additional insights into this issue.
Previous investigators of hormone therapy have believed that the addition
of MPA might somehow counteract the beneficial neurobiological or vascular
effects of estrogen.32-34 However,
in the current studies of CEE alone and CEE plus MPA, an increased risk of
dementia was found in both trials, although the difference from placebo was
significant only in the estrogen plus progestin trial. Conjugated equine estrogens
may contain estrogens with negative effects on risk of dementia, compared
with 17β-estradiol alone. However, epidemiologic studies indicating a
beneficial effect of hormones most often used CEE.32 Unless
other studies demonstrate that different compounds bestow benefit, these data
would generalize to all estrogens.35
Some studies indicate that the timing of hormone therapy may be important
in disease prevention.36 For example, in osteoporosis
the primary positive effect of hormone therapy on bone loss is found in the
immediate perimenopausal/postmenopausal period.37 Some
preclinical neurobiological studies suggest that timing of estrogen after
ovariectomy may be important in preventing neuronal loss.38,39 However,
results of the WHIMS estrogen-alone and estrogen plus progestin trials demonstrate
an increased risk of combined probable dementia or MCI associated with both
hormone regimens. Since women in the WHIMS were 65 years and older at baseline,
delayed onset of treatment relative to menopause might have allowed irreversible
neurodegeneration to occur that hormone therapy could not improve. Since the
neuropathologic abnormalities of AD develop before clinical recognition of
dementia,40 dementia prevention trials in older
women may not represent primary prevention of AD.
Approximately 45% of the women in the estrogen-alone WHIMS trial had
previously taken hormone therapy. The HR is greater than 1 for women who had
never taken hormone therapy (1.95; 95% CI, 0.94-4.04) compared with those
who had (0.87; 95% CI, 0.32-2.39); however, these differences were not statistically
significant. In the pooled analysis, the HRs of 1.95 (95% CI, 1.25-3.03) for
those who had never taken hormone therapy and 1.22 (95% CI, 0.53-2.82) for
those who had were not significantly different. Prior use of hormone therapy
did not significantly affect the results. However, a small number of events
occurred in each group.
The higher risk of dementia in women receiving estrogen alone and estrogen
plus progestin combined could be due to adverse effects of vascular disease
in the brain, as documented in epidemiologic studies. The high incidence of
stroke in both trials would be consistent with such an adverse effect of hormone
therapy on vascular disease in the brain. Earlier epidemiologic studies demonstrated
a high prevalence of silent brain infarction (25%-35%), even among older women
without a history of clinical stroke.41,42 Also,
dementia was more frequent among those who had relatively small primary lacunar
infarcts and high-grade white matter lesions, probably due to small-vessel
disease.43,44 To investigate this
further, magnetic resonance imaging will be performed on a subset of WHIMS
participants to determine the extent of subclinical neurovascular disease,
high-grade white matter infarcts and microinfarcts, and focal brain changes
consistent with early stages of AD.
Hypertension and diabetes are important determinants of vascular disease
in the brain and dementia.45-47 In
the estrogen-alone trial, hypertension was more prevalent in the CEE group
vs the matching-placebo group (42.3% and 47.3%, respectively; P = .01). Both diabetes and hypertension were associated with higher
HRs for the CEE group vs the placebo group. This was especially true for women
with diabetes assigned to CEE, in whom the HR was 1.10 (95% CI, 0.58-2.09)
for those with no history of diabetes and 9.03 (95% CI, 1.13-72.2) for those
with a history of diabetes (P = .06). The HR was
0.98 (95% CI, 0.42-2.31) for those with no history of hypertension and 2.40
(95% CI, 1.00-5.74) for those with a history of hypertension (P = .15). These comparisons may not have reached statistical significance
due to the small number of events in each subgroup. The effects of both diabetes
and hypertension were substantially less in the pooled trial data. The results
in the estrogen-alone trial, but not the pooled data, suggest a possible effect
of hypertension, diabetes, and "vascular disease" in the brain. Disease in
small vessels of the brain could be an independent determinant for risk of
dementia. More likely, the neurovascular disease emphasizes the clinical presentation
of AD in those with both vascular disease and pathologic processes consistent
with AD, leading to clinically recognized dementia.48 Thus,
an alternative hypothesis is that, in women in the early stages of AD, neurovascular
disease precipitates both dementia and MCI secondary to hormone therapy.49,50
The possibility that hormone therapy is associated with an increase
in vascular disease in the brain and incidence of dementia could have important
implications. Some participants in the estrogen-alone or estrogen plus progestin
trials may have increased neurovascular disease but have not yet developed
either MCI or dementia. Such women would remain at higher risk, not only for
dementia, but also for clinical stroke. Further follow-up of the WHIMS participants
is planned to determine whether an increased risk for dementia and MCI persists
once treatment is discontinued.
In summary, the results of the WHIMS demonstrate an increased risk of
dementia and MCI in the combined estrogen-alone and the estrogen plus progestin
trials among women between 65 and 79 years of age at study entry. Use of hormone
therapy to prevent dementia or MCI in women 65 years of age or older is not
recommended.
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